19-38717102-G-A

Position:

chr19-38717102-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004924.6(ACTN4):c.929G>A(p.Arg310Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,586 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R310W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0097 ( 16 hom., cov: 33)

Exomes 𝑓: 0.015 ( 220 hom. )

Consequence

ACTN4
NM_004924.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.57

Variant links:

Genes affected

ACTN4 (HGNC:166): (actinin alpha 4) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]

ACTN4 links:

LOC107985291 (HGNC:):

LOC107985291 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTN4. . Gene score misZ 4.1552 (greater than the threshold 3.09). Trascript score misZ 5.6825 (greater than threshold 3.09). GenCC has associacion of gene with familial idiopathic steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.00835824).

BP6

Variant 19-38717102-G-A is Benign according to our data. Variant chr19-38717102-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38717102-G-A is described in Lovd as [Benign]. Variant chr19-38717102-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00971 (1479/152350) while in subpopulation SAS AF= 0.0224 (108/4828). AF 95% confidence interval is 0.019. There are 16 homozygotes in gnomad4. There are 702 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1479 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6 linkuse as main transcript	c.929G>A	p.Arg310Gln	missense_variant	10/21	ENST00000252699.7
LOC107985291	XR_001753937.2 linkuse as main transcript	n.169+11086C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7 linkuse as main transcript	c.929G>A	p.Arg310Gln	missense_variant	10/21	1	NM_004924.6	A1	O43707-1

Frequencies

GnomAD3 genomes

AF:

0.00972

AC:

1480

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0226

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.0118

AC:

2927

AN:

248854

Hom.:

AF XY:

0.0131

AC XY:

1762

AN XY:

134858

show subpopulations

Gnomad AFR exome

AF:

0.00213

Gnomad AMR exome

AF:

0.00534

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0240

Gnomad FIN exome

AF:

0.00248

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0146

AC:

21331

AN:

1461236

Hom.:

220

Cov.:

AF XY:

0.0151

AC XY:

10964

AN XY:

726904

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00616

Gnomad4 ASJ exome

AF:

0.0115

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0241

Gnomad4 FIN exome

AF:

0.00297

Gnomad4 NFE exome

AF:

0.0158

Gnomad4 OTH exome

AF:

0.0126

GnomAD4 genome

AF:

0.00971

AC:

1479

AN:

152350

Hom.:

Cov.:

AF XY:

0.00942

AC XY:

702

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00267

Gnomad4 AMR

AF:

0.00856

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0224

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.0151

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.0145

Hom.:

Bravo

AF:

0.00965

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0130

AC:

112

ExAC

AF:

0.0119

AC:

1446

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0152

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 12, 2022	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2020	This variant is associated with the following publications: (PMID: 16251236, 27535533, 21680739) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 20, 2018	- -

Focal segmental glomerulosclerosis 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 06, 2022

- -

Intellectual disability, autosomal dominant 14

Benign:1

Likely benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The p.Arg310Gln variant in ACTN4 has been identified in at least 2 individuals with focal and segmental glomerulosclerosis, but did not segregate with disease and was also present in at least 4 unaffected individuals (PMID: 16251236). This variant has also been identified in >2% of South Asian chromosomes and 15 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg310Gln variant may impact protein function (PMID: 21680739). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant focal and segmental glomerulosclerosis. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;.;T

Eigen

Benign

-0.083

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.90

MetaRNN

Benign

0.0084

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.5

L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.2

N;N;.

REVEL

Benign

0.080

Sift

Benign

0.13

T;T;.

Sift4G

Benign

0.28

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.17

MPC

1.5

ClinPred

0.014

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.21

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over